Nur7 Is a Nonsense Mutation in the Mouse Aspartoacylase Gene That Causes Spongy Degeneration of the CNS

摘要: Aspartoacylase (ASPA) is an oligodendrocyte-restricted enzyme that catalyzes the hydrolysis of neuronally derived N -acetylaspartate (NAA) to acetate and aspartic acid. ASPA deficiency leads fatal childhood autosomal recessive leukodystrophy Canavan disease (CD). Here we demonstrate previously described ENU-induced nur7 mouse mutant caused by a nonsense mutation, Q193X, in Aspa gene ( ). Homozygous nur7nur7 mice do not express detectable protein display early-onset spongy degeneration CNS myelin with increased NAA levels similar observed CD patients. In addition, regions rich neuronal cell bodies also vacuolization. Interestingly, distinct areas, such as corpus callosum, optic nerve, spinal cord white matter appear normal nur7/nur7 mice. Reduced cerebroside synthesis has been demonstrated patients animal models. To determine potential relevance this observation pathogenesis, generated were heterozygous for null allele encodes UDP-galactose:ceramide galactosyltransferase Cgt ), which responsible catalyzing abundant galactolipids. Despite reduced amounts cerebrosides, ; +/− more severely affected than mutants, suggesting diminished major contributing factor pathogenesis. Furthermore, found significant axonal loss cerebellum older mutants. This finding suggests pathology defects may underlie neurological disabilities develop at late stages disease.